The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal ...cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the APC I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the APC I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.
Background:
Anti‐tumor necrosis factor (TNF) antibodies are efficacious in patients with Crohn's disease (CD) but the influence of these medications on surgical outcomes in CD patients has been ...frequently debated. The aim was to evaluate the impact of preoperative treatment with anti‐TNF antibodies on postoperative complications in CD patients undergoing abdominal surgery.
Methods:
A systematic review and meta‐analysis of comparative cohort studies was performed assessing postoperative complication rates in CD patients who were treated with anti‐TNF antibodies within 3 months before surgery versus patients who were not. The primary outcome was overall complication rate within 1 month of surgery. Secondary outcomes included the rate of infectious and noninfectious complications. The quality of studies was assessed based on selection of patients and controls, comparability of the study groups, and assessment of outcomes. Odds ratios (OR) with 95% confidence intervals (CIs) were computed.
Results:
A total of eight studies including 1641 patients were included in our meta‐analysis. Preoperative infliximab therapy in CD patients undergoing abdominal surgery was associated with a trend toward an increased rate of total complications (OR 1.72, 95% CI, 0.93–3.19). Anti‐TNF treatments were associated with a modestly increased risk of infectious complications (OR 1.50, 95% CI 1.08–2.08), mostly remote from the surgical site (OR 2.07 95% CI 1.30–3.30) and with a trend toward a higher rate of noninfectious complications (OR 2.00, 95% CI 0.89–4.46).
Conclusion:
Preoperative infliximab treatment is associated with an increased risk of postoperative infectious complications, mostly nonlocal. A trend toward an increased risk of noninfectious and overall complications was also observed. (Inflamm Bowel Dis 2012;)
Although the association of attention deficit hyperactivity disorder (ADHD) with psychiatric disorders is well known, its association with somatic diseases is unclear. Only few studies have ...investigated the gastrointestinal (GI) morbidity in adult patients with ADHD.
To measure gastrointestinal comorbidity and its burden on healthcare in young adults with ADHD.
The cohort included subjects aged 17-35 years recruited to the Israel Defense Forces in 2007-2013, 33380 with ADHD and 355652 without (controls). The groups were compared for functional and inflammatory conditions of the gastrointestinal tract and clinic and specialist visits for gastrointestinal symptoms/disease during service (to 2016). Findings were analyzed by generalized linear models adjusted for background variables
Compared to controls, the ADHD group had more diagnoses of functional gastrointestinal disorders (referred to as FGID), namely, dyspepsia odds ratio (OR): 1.48, 95% confidence interval (CI): 1.40-1.57,
< 0.001, chronic constipation (OR: 1.64, 95%CI: 1.48-1.81,
< 0.001), and irritable bowel syndrome (OR: 1.67, 95%CI: 1.56-1.80,
< 0.001) but not of organic disorders (inflammatory bowel disease, celiac disease). They had more frequent primary care visits for gastrointestinal symptoms rate ratio (RR): 1.25, 95%CI: 1.24-1.26,
< 0.001 and referrals to gastrointestinal specialists (RR: 1.96, 95%CI: 1.88-2.03,
< 0.001) and more episodes of recurrent gastrointestinal symptoms (RR: 1.29, 95%CI: 1.21-1.38,
< 0.001). Methylphenidate use increased the risk of dyspepsia (OR: 1.49, 95%CI: 1.28-1.73,
< 0.001) and constipation (OR: 1.42, 95%CI: 1.09-1.84,
= 0.009).
ADHD in young adults is associated with an excess of FGID and increased use of related health services. Research is needed to determine if an integrative approach treating both conditions will benefit these patients and cut costs.
In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well ...established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.
Aim
Celiac disease (CD) is a systemic disorder that is associated with various autoimmune disorders and a higher prevalence of other diagnoses and complications. This large, cross‐sectional, ...population‐based study investigated the associations between CD and various medical conditions during late adolescence.
Methods
We included 2 001 353 Jewish Israeli adolescents who underwent a general health examination at a median age of 17.1 (16.9–17.4) years from 1988 to 2015. Comprehensive data regarding medical status were available for 1 588 041 (79%) subjects. A definite diagnosis of CD was based on accepted criteria. Covariate data included demographic measures and data on associated medical conditions.
Results
Overall, data on 7145 subjects with CD and 1 580 896 controls were analysed. Multivariate analyses showed that autoimmune diseases were significantly more common in subjects with CD, including insulin dependent diabetes, with an odds ratio (OR) of 5.5, inflammatory bowel diseases (OR = 3.8), arthritis (OR = 2.4), thyroid diseases (OR = 1.8) and psoriatic skin disorders (OR = 1.6). Further associations included asthma (OR = 1.5), bile stones (OR = 3.6), migraine (OR = 2.3), anaemia (OR = 1.7) and menstrual abnormalities (OR = 1.5). Long bone fractures and axial fractures were no more common in adolescents with CD than controls.
Conclusion
CD was already associated with multiple comorbidities by adolescence, and these were not limited to autoimmune disorders.
The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk ...factors among patients with AIH.
We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I
statistic.
A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I
= 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I
= 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis.
Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis.
Abstract
Background
Growth impairment is common in pediatric inflammatory bowel disease (IBD) patients. Nevertheless, a controversy exists regarding disease impact on anthropometric measures in the ...long term. Thus, we aimed to investigate the impact of IBD on anthropometric measures, including weight, height, and body mass index (BMI), during late adolescence in a cross-sectional, population-based study.
Methods
A total of 1,144,213 Jewish Israeli adolescents who underwent a general health examination from 2002 to 2016 at a median age (interquartile range) of 17.1 (16.9-17.3) years were included. Inflammatory bowel disease cases were stratified into Crohn's disease (CD) and ulcerative colitis (UC). Patients were also subgrouped based on age at IBD diagnosis.
Results
Overall, 2372 cases of IBD were identified out of 1,144,213 persons examined (0.2%). Crohn's disease accounted for 68% of IBD cases. Males and females with CD (but not with UC) had significantly lower weight and BMI compared with controls. Differences in height at late adolescence were not statistically significant for either disease compared with controls (females: 162 cm vs 161.7 cm vs 161.5 cm; males: 174 cm vs 173.7 cm vs 173.6 cm for controls, UC, and CD, respectively). In a subgroup analysis, patients with CD diagnosed at age <14 years were significantly shorter than controls (males: 172.7 cm vs 174 cm; P = 0.001; females: 160.6 cm vs 162; P = 0.008). This pattern was not noted in UC patients.
Conclusions
Adolescents with CD were leaner compared with the general population. No overall difference was noted in height at late adolescence. Younger age at diagnosis was associated with reduced height in CD patients.
Abstract Background and aims Capsule endoscopy (CE), magnetic resonance enterography (MRE) and small bowel (SB) intestinal contrast ultrasound (SICUS) are the modalities of choice for SB evaluation. ...This study aimed to compare the diagnostic yield (DY) of CE to MRE and SICUS in detection and monitoring of SB CD through meta-analysis of the available literature. Methods We performed a systematic literature search for trials comparing the accuracy of CE, MRE and SICUS for detection of active SB inflammation in patients with suspected and/or established CD. Only prospective studies comparing CE with another additional diagnostic modality were included in the final analysis. Pooled odds ratios (ORs) for the DY of the three modalities were calculated. Results A total of 112 studies were retrieved; following selection, 13 studies were eligible for analysis. The DY of CE for detection of active SB CD was similar to that of MRE (10 studies, 400 patients, OR 1.17; 95% CI 0.83–1.67) and SICUS (5 studies, 142 patients, OR 0.88; 95% CI 0.51–1.53). The outcomes were similar for the subgroups of suspected versus established CD and adult versus pediatric patients. CE was superior to MRE for proximal SB CD (7 studies, 251 patients, OR 2.79; 95% CI 1.2–6.48); the difference vs SICUS was not significant. Conclusion CE, MRE and SICUS have similar DY for detection of SB CD in both suspected and established CD. CE is superior to MRE for detection of proximal SB disease, however the risk of capsule retention should be considered.
Targeting TGF-β signaling in cancer Katz, Lior H; Li, Ying; Chen, Jiun-Sheng ...
Expert opinion on therapeutic targets,
07/2013, Volume:
17, Issue:
7
Journal Article
Peer reviewed
Open access
The transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β ...pathway are crucial in developing TGF-β-based therapeutics for cancer.
This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given.
Targeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs.
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